PROJECT SUMMARY Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Under physiological conditions, the Notch and Wing-less/Int (Wnt) signaling pathways modulate homeostasis and differentiation of the intestinal epithelium. In intestinal cancers, these pathways are frequently dysregulated. Canonical Wnt/?- catenin signaling pathway activation, with resultant high ?-catenin transcriptional activity, is frequently implicated in human CRC; however, there are currently no treatments targeting this pathway. Several points of crosstalk between Notch and Wnt pathways have been described in CRC. Thus, uncovering the molecular mechanisms of transcriptional networks governed by the Notch and Wnt/?-catenin pathways in intestinal tumorigenesis is significant for advancing scientific knowledge on cancer biology, and would potentially provide a window for new CRC therapeutics. The long-term goal of the proposed research is to identify how transcriptional machinery controls intestinal cell differentiation and how critical transcription factors contribute to intestinal tumorigenesis. In Aims 1 and 2, using the novel transgenic mouse models and unbiased high- throughput RNA and DNA sequencing techniques, I have managed several parallel projects and multi- institutional collaborations to understand the role of transcription factor Atoh1 (Atonal homolog 1), and its downstream target, SAM Pointed Domain ETS transcription Factor (SPDEF) in CRCs. The results from the proposed project are expected to significantly advance our current understanding of transcriptional machinery in CRCs. To extend my current knowledge and gain deeper insight into the biology of cancer, in Aim 3, I plan to pursue my postdoctoral studies in the direction of understanding how these extracellular components within the tumor microenvironment contribute to the program of cancer cell metastasis, a primary cause of cancer- related fatality with CRCs, especially how these cells grow, invade, migrate, and resist treatment. Collectively, this training is customized to give me a comprehensive education in basic science research that will be extremely in achieving my long-term career goal of becoming an independent cancer researcher.